Total synthesis of antitumor acylfulvenes

ABSTRACT

A compound of formula (IV):                    
     wherein R′ and R 9  are each independently (C 1 -C 4 )alkyl.

CROSS REFERENCE TO RELATED APPLICATION

This is a divisional application of U.S. patent application Ser. No09/242,091, filed on Jan. 6, 2000, now issued as U.S. Pat. No.6,160,184, which is a U.S. National Stage Filing under 35 U.S.C. 371 ofPCT/US 97/13644, filed Aug. 5, 1997, which is a continuation of U.S.patent application Ser. No. 08/689,461, filed Aug. 8, 1996, now issuedas U.S. Pat. No. 5,723,632.

BACKGROUND OF THE INVENTION

Natural products from plants and microorganisms have proven to be amajor source of active anticancer agents and lead compounds for cancerchemotherapy. Mushrooms of the class Basidiomycetes are an exception.Although they occur widely and some are well known to contain a varietyof highly poisonous substances, only Omphalolus illudens (jack o'lanternmushroom) is known to produce promising anticancer compounds. These arethe sesquiterpenes illudin S and illudin M. The illudins are extremelycytotoxic compounds but have a low therapeutic index particularly insolid tumor systems. However, modification of their structures hasyielded several analogs, which possess a greatly improved therapeuticindex. Remarkable efficacy has been observed in tests on mousexenografts of leukemias and various solid tumors.

First and second generation analogs, for example, dehydroilludin M andacylfulvene, have been described (WO 91/04754). A promising compound isa third generation analog hydroxymethylacylfulvene (HMAF). In tests withMV 522 metastatic lung carcinoma xenografts in nude mice, complete tumorregression was observed in all animals. HMAF also exhibited outstandingactivity against breast (MX-1), colon (H-29) and skin cancers.

The structures of illudin S and illudin M were first published in 1963(McMorris et al., J. Am. Chen Soc. 85:831 (1963)). Until recently onlyone total synthesis of these compounds had been reported (Matsumoto etal., Tetrahedron Lett. 1171 (1970)). This synthesis involved Michaeladdition of a cycylopropane intermediate to an appropriately substitutedcyclopentenone. The resulting product was then transformed into anintermediate which could undergo aldol condensation to form illudin'ssix-membered ring. A number of further reactions were required tocomplete the synthesis.

Padwa et ale (J. Am. Chem. Soc. 116: 2667 (1994)), have published asynthetic approach to the illudin skeleton using a dipolar cycloadditionreaction of a cyclic carbonyl ylide dipole with cyclopentenone toconstruct the six-membered ring. Kinder and Bair (J. Org. Chem. 59:6955(1994)), have also employed the Padwa methodology to synthesize illudinM. However, these syntheses are long and not well suited for makingacylfulvenes on a large scale.

Thus, a continuing need exists for improved methods for synthesizingacylfulvenes.

SUMMARY OF THE INVENTION

The present invention provides a method of synthesizing compounds offormula (I):

wherein R and R′ are independently (C₁-C₄)alkyl, preferably methyl.According to the invention, a method is provided of synthesizing acompound of formula (V), a preferred intermediate in the synthesis ofcompounds of formula (I),:

comprising the steps of coupling a cyclopentanone of formula (II):

wherein R₄ is —O—C(R₉)₂O(R₉), wherein R₉ is (C₁-C₄)alkyl, preferablymethyl; with a cyclic carbonyl ylide dipole of formula (III):

to form a compound of formula (IV):

and treating compound (IV) with base to form a ketone of formula (V).

The present method further may further comprise the steps ofdihydroxylating the ketone to yield a compound of formula (VI):

and treating the compound of formula (VI) with a removable 1,2-diolprotecting reagent to yield an intermediate of formula (VII):

wherein X is a removable 1,2-diol protecting group. Protecting groupsmay be introduced by forming a cyclic acetal by treatment with analdehyde or ketone such as acetone, formaldehyde, acetaldehyde orbenzaldehyde. For example, an isopropylidene derivative (acetonide) maybe introduced by reaction with acetone. Preferably, the isopropylidenegroup is introduced by acid-catalyzed exchange with 2,2dimethoxypropane.

The method further comprises the steps of treating compound (VII) withRMgCl, where R is (C₁-C₄)alkyl, to yield a Grignard product of formulaVIII:

and cleaving the oxybridge to yield a diol of formula (IX):

The method further comprises the step of removing the diol protectinggroup to yield a tetraol of formula (X):

The tetraol is then converted to an orthoester of formula (XI):

wherein R″ is (C₁-C₃)alkyl; and the cis hydroxyls are eliminated toyield a dienone of formula (XII):

The method further comprises the steps of reducing the compound offormula (XII) to convert the ketone to an alcohol, under conditionswhich dehydrate the resulting alcohol to yield a fulvene of formula(XIII):

The fulvene of formula (XIII) is then oxidized to yield a compound offormula (I):

The present invention also provides a method of synthesizing a compoundof formula (XVII):

wherein R₁ is OH, R₂ is H, and R′ is (C₁-C₄)allyl, preferably methyl.

According to the present invention, a method is provided of synthesizinga diketone of formula (XIII), a preferred intermediate in the synthesisof compounds of formula (XVII),:

comprising the steps of

(a) cleaving the oxybridge in the compound of formula (XIV):

to yield a diketone of formula (XIII).

The method further comprises the steps of

(b) protecting the hydroxyl group in the compound of formula (XIII) witha removable hydroxyl protecting group X; and

(c) introducing a double bond in the five-membered ring to yield acompound of the formula (XV):

wherein R′₁ and R′₂ together are keto; and

X is a removable hydroxyl protecting group. Removable hydroxylprotecting groups may be introduced by reaction with a suitable reagent,such as a reagent of the formula ((C₁-C₄)alkyl)₃SiCl, includingtriethylsilyl (TES) chloride, trimethylsilyl (TMS) chloride,t-butyldimethylsilyl (TIBDMS) chloride, dimethyl(1,2,2-trimethylpropyl)silyl chloride, or tris(isopropyl)silyl; andmethoxymethyl chloride, β-methoxyethoxymethyl chloride, and isobutylene.

The method further comprises the steps of

(d) reducing both keto groups to yield hydroxy groups under conditionsthat yield a compound of formula (XVI):

(e) eliminating the cyclopentenol hydroxyl group; and

(f) oxidizing the cyclohexanol hydroxyl group and removing hydroxylprotecting group X to yield a compound of formula (XVII):

wherein R₁ is OH and R₂ is H.

The method additionally comprises the step of

(g) following step (d), treating the alcohol with mesyl chloride in thepresence of a base to produce a mesylate of the formula (XVIII):

wherein R″₁ is —OX, R″₂is absent and R is H.

The present invention further provides a method of synthesizingcompounds of the formula (XXIII):

wherein R′₁ and R′₂ together are ethylenedioxy, and R′ is (C₁-C₄)alkyl,preferably methyl.

According to the present method, the carbonyl group of the compound offormula (XIII) is converted to an acetal group to yield a compound offormula (XIX):

The method further comprises the steps of

(b) protecting the hydroxyl group in the compound of formula (XIX) witha removable hydroxyl protecting group X; and

(c) introducing a double bond in the five-membered ring to yield acompound of the formula (XX):

wherein X is a removable hydroxyl protecting group.

The method further comprises the steps of

(d) reducing the keto group to yield a hydroxy group under conditionsthat yield a compound of formula (XXI):

(e) eliminating the cyclopentenol hydroxyl group;

(f) removing hydroxyl protecting group X to yield a compound of formula(XXII):

and

(g) oxidizing the cyclohexanol hydroxyl group to yield a compound offormula (XXIII):

The method further comprises the step of

(h) following step (d), treating the alcohol with mesyl chloride toproduce

a mesylate of the formula (XXIV):

With respect to both mesylates of formulas (XVIII) and (XXIV), themesylates are relatively unstable and convert to fulvenes upon standing.Removal of the protecting group X and oxidation yield compounds offormulas (XVII) and (XXIII), respectively.

The invention also provides novel compounds of formula I-XXIV, all ofwhich are useful as intermediates in the synthesis of 6-substitutedacylfulvene analogs (6-substituted acylfulvenes) as disclosed, forexample, in Kelner et al., U.S. Pat. No. 5,523,490, or which haveantitumor or cytotoxic activity per se.

BRIEF DESCRILITON OF THE DRAWINGS

FIG. 1 is a schematic representation of the synthesis of a compound ofFormula (I), specifically compound 26.

FIG. 2 is a schematic representation of the synthesis of compound ofFormula (XV), specifically compound 35.

FIG. 3 is a schematic representation of the synthesis of compound ofFormula (XV), specifically compound 42.

DETAILED DESCRIPTION OF THE INVENTION

An illudin analog of formula (I), where R and R′ are methyl (compound26), can be synthesized by utilizing FIG. 1. The numbers following thenamed compounds refer to the numbered compounds of Schemes I, II andIII. The staring compound (14) is readily prepared from furfural andmethylmagnesium chloride followed by acid catalyzed rearrangement(Piancatelli et al., Tetrahedron Lett. 3555 (1976)). Protection of thehydroxyl in 14 by forming the acetal derivative 15, for example,followed by reaction with ylide 5 gives the adduct 16 (84% yield). Mildbase treatment (KOH—MeOH, room temp., 1 h) of 16 affords the unsaturatedketone 17 (95%). Dihydroxylation of 17 with OsO₄, NMO in THF (roomtemp., 24 h) gives the cis-dihydroxy product 18 which is converted tothe acetonide 19 with dimethoxy propane and p-TsOH (87% for the twosteps). Regioselective reaction of 19 with methylmagnesium chloride (inTHF, −78° C.) affords the Grignard product 20. Treatment of 20 with 10%KOH—MeOH at 80° C. for 2 h cleaves the oxybridge giving the diol 21 (75%for the two steps). The structure (21) has been confirmed by X-raycrystallographic analysis which indicates trans relationship of the twohydroxyls.

Hydrolysis of the acetonide with Dowex resin (He form) in MEOH at roomtemperature for 12 h affords the tetraol 22 in 95% yield. Conversion of22 to the orthoester 23 by treatment with trimethylorthoformate andp-TsOH at room temperature followed by heating 23 at 19° C. underreduced pressure results in elimination of the cis hydroxyls yieldingthe dienone. The yields in this reaction are rather low but can beimproved by adding acetic anhydride. A good yield of the monoacetate anddiacetate (24 a, b) is obtained. Reduction of the ketone withNaBH₄—CeCl₃ gives the corresponding alcohol which is unstable and isconverted to the fulvene on standing. The acetate groups are removed bytreatment with lithium aluminum hydride and the resulting fulvene 25 isoxidized with the Dess-Martin reagent to ±acylfulvene 26. The overallyield for the last four steps is approximately 30%.

An acylfulvene analog of formula (XV) where R′₁ and R′₂ together areethylenedioxy (compound 35), may be synthesized as shown in FIG. 2. Theoxybridge in the intermediate 7 is cleaved with K₂CO₃ in isopropanol atroom temperature giving the diketone 27 (82%). Regioselective acetalformation (ethylene glycol, p-TsOH, C₆H₆, room temperature) gives inquantitative yield the monoacetal 28. Protection of the hydroxyl as thetriethyl silyl ether (triethylsilylchloride, pyridine, 60° C.) isquantitative. A double bond is introduced into compound 29, by treatmentwith benzene seleninic anhydride in chlorobenzene at 95° C., yieldingcross conjugated ketone 30 (78%). Reduction of 30 (NaBH₄, CeCl₃. 7H₂O inMeOH) gives alcohol 31. This compound on treatment with methane sulfonylchloride and triethylamine gives the fulvene 33 (via the unstablemesylate 32). Removal of the silyl protecting group (p-TsOH,acetone-water 1:1) gives the alcohol 34, which upon oxidation withpyridinium dichromate in dichloromethane affords the acylfulvene 35 (60%yield for four steps).

Another analog of formula (XVII) where R₁ is OH and R₂ is H (compound42) can be made from intermediate 27. As shown in FIG. 3, compound 27 isconverted to the triethylsilyl (TES) ether 36. A double bond is thenintroduced in the five membered ring by reaction with phenylseleninicanhydride giving 37 in good yield. Reduction of the diketone with sodiumborohydride-ceric chloride gives the corresponding alcohols accompaniedby rearrangement of the TES group, resulting in compound 38. Treatmentof the latter with triethylamine and mesylchloride gives the unstablemesylate 39 which directly yields the fulvene 40. Oxidation of 40 withDess-Martin reagent and removal of the silyl protecting group gives±acylfulvene analog 42.

The compounds of formulas (I), (XVII) and (and intermdiates thereof areuseful as antineoplastic agents, i.e., to inhibit tumor cell growth invitro or in vivo, in mammalian hosts, such as humans or domesticanimals, and are particularly effective against solid tumors andmulti-drug resistant tumors. These compounds may be particularly usefulfor the treatment of solid tumors for which relatively few treatmentsare available. Such tumors include epidermoid and myeloid tumors, acute(AML) or chronic (CML), as well as lung, ovarian, breast and coloncarcinoma. The compounds can also be used against endometrial tumors,bladder cancer, pancreatic cancer, lymphoma, Hodgkin's disease, prostatecancer, sarcomas and testicular cancer as well as against tumors of thecentral nervous system, such as brain tumors, neuroblastomas andhematopoietic cell cancers such as B-cell leukemia/lymphomas, myelomas,T-cell leukemia/lymphomas, and small cell leukemia/lymphomas. Theseleukemia/lymphomas could be either acute (ALL) or chronic (CLL).

The compounds may also be incorporated in a pharmaceutical composition,such as pharmaceutical unit dosage form, comprising an effectiveanti-neoplastic amount of one or more of the illudin analogs incombination with a pharmaceutically acceptable carrier.

The methods of the present invention may also be adapted to makepharmaceutically acceptable salts of compounds of formula (I), (XVII) or(XXIII). Pharmaceutically acceptable salts include, where applicable,salts such as amine acid addition salts and the mono-, di- andtriphosphates of free hydroxyl groups. Amine salts include salts ofinorganic and organic acids, including hydrochlorides, sulfates,phosphates, citrates, tartarates, malates, maleates, bicarbonates, andthe like. Alkali metal amine or ammonium salts can be formed by reactinghydroxyaryl groups with metal hydroxides, amines or ammonium.

The compounds can be formulated as pharmaceutical compositions andadministered to a mammalian host, such as a human cancer patient, in avariety of forms adapted to the chosen route of administration, i.e.,orally or parenterally, by intravenous, intraperitoneal, intramuscularor subcutaneous routes.

The subject can be any mammal having a susceptible cancer, i.e., amalignant cell population or tumor. The analogs are effective on humantumors in m as well as on human tumor cell lines in vitro.

Thus, the compounds may be orally administered, for example, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. They may be enclosed in hardor soft shell-gelatin capsules, may be compressed into tablets, or maybe incorporated directly with the food of the patient's diet. For oraltherapeutic administration, the active compound may be combined with oneor more excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be between 2to about 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage level will be obtained.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose, or saccharin or a flavoring agent such as peppermint,oil of wintergreen, or cherry flavoring may be added. When the unitdosage form is a capsule, it may contain, in addition to materials ofthe above type, a liquid carrier, such as a vegetable oil or apolyethylene glycol. Various other materials may be present as coatingsor to otherwise modify the physical form of the solid unit dosage form.For instance, tablets, pills, or capsules may be coated with gelatin,wax, shellac or sugar and the like. A syrup or elixir may contain theactive compound, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and flavoring such as cherry ororange flavor. Of course, any material used in preparing any unit dosageform should be pharmaceutically acceptable and substantially nontoxic inthe amounts employed. In addition, the active compound may beincorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound can be prepared in water, optionally mixed with a nontoxicsurfactant Dispersions can also be prepared in glycerol, liquidpolyethylene glycols, triacetin, and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion usecan include sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable of infusible solutionsor dispersions. In all cases, the ultimate dosage form must be sterile,fluid and stable under the conditions of manufacture and storage. Theliquid carrier or vehicle can be a solvent or liquid dispersion mediumcomprising, for example, water, ethanol, a polyol (for example,glycerol, propylene glycol, liquid polyethylene glycols, and the like),vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.The proper fluidity can be maintained, for example, by the formation ofliposomes, by the maintenance of the required particle size in the caseof dispersion or by the use of surfactants. The prevention of the actionof microorganisms can be brought about by various antibacterial andantifungal agents, or example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin. Sterileinjectable solutions are prepared by incorporating the active compoundin the required amount in the appropriate solvent with various of theother ingredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

Useful dosages of compounds made according to the present methods can bedetermined by correlating the compounds' in vitro activity, and in vivoactivity in animal models, such as murine or dog models as taught forilludin analogs such as those of U.S. Pat. Nos. 5,439,936 and 5,523,490,to activity in higher mammals, such as children and adult humans astaught, e.g., in Borch et al. (U.S. Pat. No. 4,938,949).

The therapeutically effective amount of analog necessarily varies withthe subject and the tumor to be treated. However, it has been found thatrelatively high doses of the analogs can be administered due to thedecreased toxicity compared to illudin S and M. A therapeutic amountbetween 30 to 112,000 μg per kg of body weight is especially effectivefor intravenous administration while 300 to 112,000 μg per kg of bodyweight is effective if administered intraperitoneally. As one skilled inthe art would recognize, the amount can be varied depending on themethod of administration.

The invention will be further described by reference to the followingdetailed examples.

EXAMPLES Example I

Synthesis of Compound 36

General.

Solvents were dried and distilled prior to use. THF and diethyl etherwere distilled from sodium-benzophenone, CH₂Cl₂ and triethylamine fromCaH₂, Melting points are uncorrected. 1H— and 13C—NMR spectra weremeasured at 300 MHz and 75 MHz, respectively. High resolution massspectra were determined at 70 ev (EI) by the Mass Spectrometry ServiceLaboratory at the University of Minnesota Column chromatography wasperformed on silica gel (Davisil 230-425 mesh, Fisher Scientific ). Insome cases, a small amount of triethylamine was used to neutralize thesilica gel.

Compound 15.

To a solution of 14 (0.448 g, 4 mmol) in 2-methoxypropene (1.55 ml, 16.2mmol), a drop of POCl₃ was added under Ar. The solution was stirred at25° C. for 12 hours and quenched by 3 drops of Et₃N. The volatilecomponents were removed in vacuo and the product 15 was obtained as abrown liquid which crystallized below 0° C. (0.69 g, 94.3%). ¹H NMR(CDCl₃): δ 7.43(dd, 1H), 6.17(d, 1H), 4.58(br s, 1H), 3.26(s, 3H),2.26(m, 1H), 1.41(s, 3H), 1.40(s, 3H), 1.22(d, 3H).

Compound 16.

To a mixture of 15 (5.02 g, 27.3 mmol), rhodium acetate (145 mg, 0.33mmol), DMF(500 uL) in CH₂Cl₂(50 mL), a solution of 4 (6.0 g, 39.5 mmol)in CH₂Cl₂ (50 mL) was added dropwise within 10 minutes at 40° C. Theorange-red solution was refluxed at 40° C. for 1.5 hours and the solventwas removed in vacuo. Chromatography (Hexane/EtOAc, 10:2) gave product16 as white crystals (7.10 g, 84.5%). m.p.: 142-144° C.; ¹H NMR (CDCl₃):δ 4.98(s, 1H), 4.13(dd, 1H), 3.28(s, 3H), 2.82(t, 1H). 2.63(d, 1H),2.54(m, 1H), 1.43(s,3H), 1.42(s,3H), 1.18(s, 3H), 1.08(d, 3H). 1.29(m,1H), 1.03-1.16(m, 2H), 0.72(m, 1H); ¹³C NMR (CDCl₃): δ 213.3, 212.1,101.2, 87.4, 81.8, 73.8, 59.4, 50.4, 49.7, 45.8, 39.0, 26.0, 25.1, 14.1,13.7, 12.4, 11.4. IR (film, cm⁻¹): 2985, 1738, 1389, 1339, 1173, 1080,1052, 991, 859, 827; HRMS calcd. for C₁₇H₂₄O₅: 308.1624, found:308.1625.

Compound 17.

The solution of 16 (594.3mg, 1.93 mmol) in 5% KOH—MeOH (35 ml) wasstirred at room temperature for 1 hour. The generated red solution wasthen neutralized and extracted with EtOAc. The combined organic phasewas washed with sat. brine (20 ml×2) and dried over Na₂SO₄.Chromatography (Hexanes/EtOAc, 10:3)gave the product 17 as whitecrystals (390.9 mg, 93%).m.p.: 108.5-109.4C; ¹H NMR (CDCl₃): δ 7.15(d,1H), 4.24(s, 1H), 3.21(br s, 1H), 2.55(d, 1H), 1.75(s, 3H), 1.23(s, 3H),1.25(m, 1H), 1.10(m, 1H), 0.97(m, 1H), 0.74(m, 1H); ¹³C NMR (CDCl₃): δ211.77, 205.86, 154.23, 145.86, 86.05, 80.93, 54.68, 45.82, 37.56,14.05, 13.22, 11.58, 10.22; IR (film, cm⁻¹): 1754, 1703, 1639, 1389,1339, 997; HRMS calcd. for C₁₃H₁₄O₃: 218.0943, found: 218.0941.

Compound 19.

To a solution of 17 (349.4 mg, 1.60 mmol), NMO (355 mg) in THF (17.7 ml)and H₂O (0.5 ml), was added OsO₄-THF solution (2.5wt %, 3.5 ml). Afterstirred at 25° C. for 21hrs, the reaction was quenched by aqueous Na₂SO₃solution. The reaction mixture was extracted with EtOAc. The organicphase was washed with sat. NaCl solution, dried over Na₂SO₄ andconcentrated. The crude diol product 18 was used for next step withoutfurther purification. A small amount of 18 was purified bychromatography. ¹H NMR (CDCl₃): δ 4.60(s,1H), 3.95(t, 1H), 3.01(d, 1H),2.94(d, 1H), 2.88(s, 1H), 2.81(dd, 1H), 1.36(s, 3H), 1.28(s, 3H),1.33(m, 1H), 1.18(m, 1H), 1.06(m, 1H), 0.75(m, 1H).

The crude diol 18 was reacted with 2,2dimethoxypropane (0.8 ml, 4eq.) inCH₃CN (8.0 ml) in the presence of a trace of pTsOH. After being stirredat 25° C. for 10 hrs, the mixture was diluted with CH₂Cl₂ and washedwith sat NaHCO₃ solution and brine. Chromatography (Hexanes/EtOAc, 10:2)gave the product 19 as white crystals (308.5 mg, 87.3%). m.p.:178.5-179.5° C.; ¹H NMR (CDCl₃): δ 4.58(s, 1H), 4.36(s, 1H), 2.89(q,2H), 1.42(s, 3H), 1.34(s, 3H), 1.31(s, 3H), 1.20(s, 3H), 1.28(m, 1H),1.16(m, 1H), 1.05(m, 1H), 0.69-0.76(m, 1H); ¹³C NMR (CDCl₃): δ 215.53,210.05, 110.66, 87.96, 86.44, 85.03, 83.34, 57.36, 45.37, 38.49, 27.17,25.96, 16.92, 14.19, 13.57, 12.32; IR (film, cm⁻¹): 2986, 1746, 1372,1338, 1247, 1216, 1158, 1082; HRMS calcd. for C₁₆H₂₀O₅: 292.1311, found:292.1315.

Compound 21.

To the solution of 19 (289.5mg, 0.99 mmol) in THF (25 ml) at −78° C.,was added MeMgCl-THF solution (3.0M, 830 μl, 2.5 eq) slowly. After 2.5hrs, the solution was warmed to 0° C. and quenched with sat. NH₄Clsolution. The solution was extracted with EtOAc and the organic phasewas washed with brine solution. Concentration of dried organic solutiongave the crude compound 20. ¹H NMR (CDCl₃): δ 4.29(s, 1H), 4.23(s, 1H),3.45(d, 1H), 2.78(d, 1H), 1.39(s, 3H), 1.35(s, 3H), 1.33(s, 3H), 1.24(s,3H), 1.01(s, 3H), 0.77(m, 1H), 0.67(m, 1H), 0.52(m, 1H), 0.20(m, 1H); IR(film, cm⁻¹): 3492, 2984, 2934, 1743, 1454, 1373, 1257, 1210, 1159,1082; HRMS calcd. for C₁₇H₂₄O₅: 308.1624, found: 308.1629.

The crude compound 20 was dissolved in 10% KOH-MeOH solution. The redmixture was heated at 80° C. for 2 hrs then partitioned between H₂O andCH₂Cl₂. The organic layer was washed with brine then dried over Na₂SO₄.Chromatography (Hexanes/EtOAc, 10:15) gave the product 21 as whitecrystals (228.0 mg, 75%) (inseparable mixture of isomers shown by ¹HNMR). m.p.: 162.0-164.0° C.; ¹H NMR (CDCl₃): δ 4.52(d, 1H), 3.88(dd,1H), 3.38(m, 1H), 2.33(d, 1H), 2.18(s, 1H), 1.81(d, 3H), 1.42(s, 3H),1.38(s, 3H), 1.07(s, 3H), 0.97-1.18(m, 4H); ¹³C NMR (CDCl₃): δ 201.52,152.89, 126.44, 112.96, 85.95, 81.34, 73.14, 72.31, 44.44, 29.41, 28.71,28.22, 22.82, 21.07, 14.11, 12.58, 7.58; IR (film, cm⁻¹): 3455, 2987,2935, 1694, 1599, 1445, 1373, 1240, 1212, 1092, 1048; HRMS calcd forC₁₇H₂₄O₅: 308.1624, found: 308.1624.

Compound 22.

The compound 21 (60.9 mg, 0.20 mmol) was stirred with Dowex 50w-x16resin (2.96 g) in MeOH (5.0 ml) at r.t. for 22 hrs. The resin wasfiltered away and the filtrate was washed with sat NaHCO₃, sat NaCl anddried over Na₂SO₄. Chromatography (CH₂Cl₂/MeOH, 10:1) gave the productas white crystals (49.5 mg, 93%). m.p.: 149.0-151.0° C.; ¹H NMR (CD₃OD):δ 3.83(d, 1H), 3.81(s, 1H), 3.25(m, 1H), 1.90(d, 3H), 1.25(s, 3H),1.07(s, 3H), 0.99-1.11(m, H); ¹³C NMR (CD₃OD): δ 202.95, 156.24, 127.16,76.44, 74.38, 74.12, 71.69, 4.52, 30.07, 23.14, 20.03, 14.56, 13.30,8.20; HRMS calcd. for C₁₄H₂₀O₅: 68.1311, found: 268.1312.

Compound 24a and 24b.

To the solution of 22 (40.2 mg, 0.15 mmol) and pTsOH (3.0 mg) in THF(3.0 ml), was added HC(OCH₃)₃(130 μl, 8 eq.) at 25° C. After 2 hrs, sat.NaHCO₃ solution was added and the mixture was extracted with EtOAc. Thecombined organic phase was washed with brine and dried over Na₂SO₄.Concentration of the filtrate gave the ortho ester 23 (46.3 mg, 100%) asthe intermediate for next reaction.

The ortho ester 23 (35.7 mg, 0.12 mmol) in Ac₂O (2.0 ml) was heated at150° C. for 1 hr. To the cooled reaction solution was added sat NaHCO₃solution and extracted with EtOAc. The organic phase was washed withbrine and dried over Na₂SO₄. chromatography (Hexanes/EtOAc, 10:3 to10:7) gave the products 24a and 24b as white crystals in 57.3% (18.2 mg)and 9.8% (3.6 mg) respectively.

Product 24a:

m.p.: 119-121° C.; ¹H NMR (CDCl₃): δ 6.98(s, 1H), 5.25(d, 1H), 3.92(brs, 1H), 1.95(s, 3H), 1.92(s, 3H), 1.80(t, 3H), 0.94-1.42(m,4H); ¹³C NMR(CDCl₃): δ 195.59, 170.87, 147.53, 145.85, 145.25, 128.16, 74.16, 72.64,41.02, 30.30, 22.93, 20.89, 13.48, 11.19, 11.00, 7.70; IR (film, cm⁻¹):3431, 2982, 2914, 1735, 1671, 1613, 1437, 1374, 1237, 1222, 1086, 1027;HRMS calcd. for C₁₆H₂₀O₄: 276.1362, found: 276.1363.

Product 24b:

mp.: 1893-1912° C.; ¹H NMR (CDCl₃): δ 6.95(s, 1H), 6.12(d, 1H), 3.49(brs, 1H), 2.00(s, 3H), 1.97(s, 3H), 1.92(s, 3H), 1.79(s, 3H), 1.30(s, 3H),0.92-1.27(m, 4H); ¹³C NMR (CDCl₃): δ 195.35, 170.17, 170.35, 146.76,146.00, 145.47, 127.95, 83.75, 70.53, 41.12, 29.27, 22.38, 20.78, 17.23,12.35, 11.39, 10.95, 9.11.

Compound 26 Acylfulvene from 24a.

To the clear solution of 24a (2.3 mg, 8.8 umol), CeCl₃.7H₂O (24.9 mg,8.0 eq) in Methanol (78 ul) and THF (155 ul) at 0° C., excess of NABH,was added in one portion After 15 minutes at 0° C., the suspenson wasstirred at 25° C. for 30 minutes. At 0° C., the mixture was quenchedwith 5% HCl solution and Sat.NH4Cl solution and extracted with CH₂Cl₂.The organic phase was washed with H₂O and dried over MgSO₄.Concentration and chromatography (Hexanes/EtOAc, 10:5) gave the productas yellow solid (1.8 mg, 84%). ¹H NMR (CDCl₃): δ 6.06(s, 1H), 6.01(s,1H), 5.84(s, 1H), 2.21(s, 3H), 2.04(s, 3H), 1.81(s, 3H), 1.15(s, 3H),0.62-1.44(m, 4H);

The yellow compound was then dissolved in absolute ethanol (100 ul) anda trace of KCN was added. The solution was stirred overnight at 25° C.and TLC showed the compound 25 was the exclusive product. The solutionwas diluted with ether and washed with sat.brine and dried over Na₂SO₄.

After concentration, the crude diol 25 was oxidized by Dess-Martinreagent (11.8 mg) in CH₂Cl₂ solution (1.2 ml). After being stirred at25° C. for 1 hour, the reaction solution was diluted with ether andquenched with the mixture of aqueous sodium bicarbonate and sodiumbisulfite. The organic phase was washed with sat. NaHCO₃ and sat NaClsolution and dried over NaSO₄. Concentration and chromatography(Hexanes/EtOAc, 10:1) gave product 26 Acylfulvene as a yellow gum (1.1mg, 47% from 24a). ¹H NMR (CDCl₃): δ 7.16(s, 1H), 6.43(t, 1H), 2.15(s,3H), 2.00(s, 3H), 1.38(s, 3H), 0.70-1.55(m, 4H); IR (film, cm⁻¹): 3464,2922, 2851, 1723, 1664, 1610, 1487, 1441, 1355, 1327, 1264, 1095, 1031;HRMS calcd. for C₁₄H₁₆O₂: 217.1229(M+H⁺), found: 217.1224(M+H⁺).

Compound 26 Acylfulvene from 24b.

To the clear solution of 24b (4.1 mg, 0.013 mmol), CeCl₃.7H₂O (39.5 mg,0.11 mmol) in Methanol (100 ul) and THF(200 ul) at 0° C., excess ofNABH₄ was added in one portion. After 1 hour at 0° C., the suspensionwas stirred at 25° C. for 15 minutes. At 0° C., the mixture was quenchedwith 5% HCl solution and Sat.NH4Cl solution and extracted with CH₂Cl₂.The organic phase was washed with H₂O and dried over MgSO₄.Concentration and chromatography (Hexanes/EtOAc, 10:3) gave the productas yellow solid (3.9 mg, 100% ). ¹H NMR (CDCl₃): δ 6.24(s, 1H), 6.18(s,1H), 6.02(d, 1H), 2.06(s, 3H), 2.03(s, 3H), 1.89(s, 3H), 1.82(s, 3H),1.50(s, 3H), 1.39(m, 1H), 0.99-1.07(m, 3H);

The yellow solid (3.0 mg, 0.01 mmol) was redissolved in ether (0.6 ml)and added to the reaction vial with LiAlH₄ (12 mg, 0.31 mmol) in ether(0.4 ml) at 0° C. The suspension was stirred at 0° C. for 30 minutes andwarmed up to 25° C. for 20 minutes. The reaction was quenched withacetone then 5% HCl solution and sat NH₄Cl solution were added. Themixture was extracted with ether. The combined ether phase was washedwith sat. NaCl solution and dried over NaSO₄. Remove of solvent gave thecrude diol 25.

The crude diol 25 was oxidized by Dess-Martin reagent (70 mg) in CH₂Cl₂solution (1.5 ml). After being stirred at 25° C. for 1 hour, thereaction solution was diluted with ether and quenched with the mixtureof aqueous sodium bicarbonate and sodium bisulfite. The organic phasewas washed with sat. NaCO₃ and sat NaCl solution and dried over NaSO₄.Concentration and chromatography (Hexanes/EtOAc, 10:1) gave product 26Acylfulvene as a yellow gum (0.7 mg, 33% from 24b). ¹H NMR (CDCl₃): δ7.16(s, 1H), 6.43(t, 1H), 2.15(s, 3H), 2.00(s, 3H), 1.38(s, 3H),0.70-1.55(m, 4H); IR (film, cm⁻¹): 3464, 2922, 2851, 1723, 1664, 1610,1487, 1441, 1355, 1327, 1264, 1095, 1031; HRMS calcd. for C₁₄H₁₆O₂:217.1229 (M+H⁺), found: 217.1224 (M+H⁺).

Example II

Synthesis of Compound 35

General.

Melting points are uncorrected. ¹H and ¹³C NMR spectra were measured at300 and 75 MHz. High resolution mass spectra were determined at theUniversity of Minnesota Mass Spectrometry Service Laboratory. Allchromatography used silica gel (Davisil 230-425 mesh, Fisher Scientific)and solvent was ethyl acetate and hexanes. Analytical TLC was carriedout on Whatman 4420 222 silica gel plates. Reactions were routinelymonitored by TLC. Yield was calculated after recycling startingmaterials.

Compound 7.

Compound 7 was made following literature as a white solid: mp 134-6° C.;IR (KBr) 2993, 2952, 1757, 1743, 1454 cm⁻¹; ¹H NMR (CDCl₃) δ 0.74 (m,1H), 1.03 (m, 1H), 1.13 (m, 1H), 1.25 (s, 3H), 1.32 (m, 1H), 2.08 (m,2H), 2.27 (m, 2H), 2.54 (d, J=7.5 Hz, 1H), 2.92(m, 1H), 4.45 (s, 1H);¹³C NMR (CDCl₃) δ 216.6, 211.4, 87.7, 87.4, 57.6, 41.3, 39.2, 38.3,25.1, 14.1, 13.4, 11.9; MS m/z 206 (M⁺), 177, 149, 124; BRMS forC₁₂H₁₄O₃ calcd 206.0943, found 206.0941.

Compound 27.

To a stirred solution of 7 (2.83 g, 13.7 mmol) and 2-propanol (500 ml)was added K₂CO₃ (8 g, 58.0 mmol) at 25° C. The mixture was stirred for 7days, then partitioned between EtOAc and water. The organic extract waswashed with saturated NH₄Cl and dried over MgSO₄. Then the crude productwas concentrated and chromatographed to give 1.88 g of 7 and 0.78 g of27 (82.1%). 27 is a white solid: mp 183-5 IC; IR (KBr) 3369, 2995, 1696,1616, 1407, 1367, 1226 cm⁻¹; ¹HNMR (CDCl₃) δ 1.24 (m, 1H), 1.38 (m, 1H),1.68 (m, 1H), 1.88 (m, 1H), 2.00 (s, 3H), 2.16 (m, 2H), 2.46 (m, 2H),3.21 (m, 1H), 4.06 (d, J=2.7 Hz, 1H); ¹³C NMR (CDCl₃) δ 206.1, 204.8,147.5, 128.0, 72.0, 42.2, 39.5, 32.1, 21.7, 19.4, 18.6, 11.7; MS m/z 206(M⁺), 177, 150, 147; HRMS for C₁₂H₁₄O₃ calcd 206.0943, found 206.0944.

Compound 28.

p-Tolunesulfonic acid (12 mg, 0.063 mmol) was added to a stirredsolution of 27 (107 mg, 0.519 mmol) and ethylene glycol (3.04 g, 49mmol) in benzene (10 ml) at 25° C. which was then stirred for 24 h. Themixture was partitioned between EtOAc and saturated NaHCO₃. The combinedorganic layers were washed with saline, dried over MgSO₄ andconcentrated to an oil which was chromatographed to give 5 mg of 27 and118 mg of 28 (95.3%) as colorless oil: IR (KBr) 3469, 2952, 2892, 1757,1690, 1616, 1374, 1159, 1085 cm⁻¹; ¹H NMR (CDCl₃) δ 1.00 (m, 3H), 1.36(m, 1H), 1.88 (d, J=2.7 Hz, 3H), 1.96 (m, 2H), 236 (m, 2H), 3.19 (t,J=3.9 Hz, 1H), 3.78 (t, J=3.9 Hz, 1H), 4.00 (m, 4H); ¹³CNMR(CDCl₃) δ205.4, 148.3, 128.3, 108.9, 67.9, 65.6, 64.5, 41.9, 39.3, 26.8, 20. 8,12.8, 11.5, 6.22; MS m/z 250 +), 221, 193, 177; HRMS for C₁₄H₁₈O₄ calcd250.1205, found 250.1201.

Compound 29.

To a stirred solution of 28 (8.0 mg, 0.032 mmol) and pyridine (0.5 ml)was added TESCl (0.1 ml, 0.25 mmol) under N₂. The reaction mixture wasstiffed at 60° C. for 30 min and then concentrated to an oil. The crudeproduct was purified by chromatography to give 13 mg of 29(quantitative) as a colorless oil: IR (KBr) 2959, 2885, 1710, 1610,1454, 1414, 1381, 1219 cm⁻¹; ¹H NMR (CDCl₃) δ 0.62 (q, J=7.8 Hz, 6H),0.94 (m, 1H), 1.28 (m, 1H), 1.83 (m, 1H), 1.87 (d, J=2 Hz, 3H), 2.35 (m,2H), 3.13 (m, 2H), 3.75 (d, J=3.3 Hz, 1H), 4.01 (m, 4H); ¹³C (CDCl₃) δ205.6, 148.8, 128.8, 109.5, 69.1, 65.3, 64.7, 43.3, 39.5, 27.4, 21.5,12.9, 11.6, 6.8, 6.5, 4.8; MS m/z 364 (M⁺), 336.291, 219, 161; HRMS forC₂₀H₃₂O₄Si calcd 364.2070, found 364.2070.

Compound 30.

A solution of 29 (13 mg, 0.0357 mmol) and phenylseleninic anhydride (13mg, 0.0361 mmol) in chlorobenzene (0.5 ml) was stirred at 95° C. for 0.5h under N₂. The solution was then concentrated and chromatographed togive 4.9 mg of 29 and 7.0 mg of 30 (78.2%) as colorless oil: IR (KBr)2959, 2878, 1716,1683, 1622, 1454, 1381, 1213 cm⁻¹; ¹H NMR (CDCl₃) δ0.54 (q, J=6.3 Hz, 6H), 0.89 (m, 10 H), 1.27 (m, 2H), 1.57 (m, 1H), 1.93(m, 3H), 3.79 (s, 1H), 4.00 (m, 4H), 6.30 (dd, J=2.4, 6 Hz, 1H), 7.28(dd, J=2.1, 6 Hz, 1H); ¹³C NMR (CDCl₃) δ 195.9, 154.7, 146.9, 137.7,127.5, 109.5, 69.2, 65.5, 64.6, 47.4, 28.0, 12.8, 11.1, 7.1, 6.7, 5.0;MS m/z 362 (M⁺), 333, 289,. 187, 159, 87; HRMS for C₂H₃₀O₄Si calcd362.1913, found 362.1919.

Compound 34.

To the solution of 30 (20 mg, 0.055 mmol) and CeCl₃.7H₂O (35 mg, 0.094mmol) in MeOH (1 ml) was added NaBH₄ (excess). The mixture was stirredfor 15 min at 25° C. and then more NaBH₄ was added. After 15 min ofstirring the mixture was partitioned between Et₂O and saturated NH₄Cl.The ether extract was dried over MgSO₄ and concentrated to give crudeproduct 31 as pale yellow oil.

To the solution of the above crude product 31 in CH₂Cl₂(1 ml) was addedEt₃N (20 ml, 0.143 mmol) and MsCl (20 ml, 0.258 mmol) respectively at25° C. It was stirred for 5 min Then the mixture was partitioned betweenEt₂O and saturated NaHCO₃. The ether extract was washed by saline anddried over MgSO₄. After concentration, it was chromatographed to give 33and 34 as yellow gum.

To the solution of the above compound 33 in acetone (2 ml) and water (1ml) was added some p-TsOH at room temperature. The mixture was set asidefor 5 min and partitioned between Et₂O and saturated NaHCO₃. Then theether extract was washed by saline and dried by MgSO₄. Afterconcentration and chromatography, it was mixed with the above product 34to give 10.5 mg of 34 as yellow gum: IR (KBr) 3456, 2912, 2885, 1730,1636, 1441, 1367 cm⁻¹; ¹H NMR (CDCl₃) δ 0.75 (m, 1H), 1.10 (m, 2H), 1.24(m, 1H), 1.88(s, 3H), 2.34 (d, J=6.9 Hz, 1H), 3.95 (m, 2H), 4.06 (m,2H),4.68 (d, J=5.7 Hz, 1H), 6.34 (m, 1H), 6.42 (m, 2H); ¹³C NMR (CDCl₃)δ 152.0, 139.8, 134.6, 130.5, 125.3, 117.9, 111.9, 71.3, 67.0, 66.1,31.5, 16.4, 9.5, 6.6; MS m/z 232 (M⁺), 215, 189, 160, 145; HRMS forC₁₄H₁₆O₃ calcd 232.1099, found 232.1093.

Compound 35.

A solution of 34 (7.3 mg, 31 mmol) and pyridinium dichromate (26 mg, 69mmol) in CH₂Cl₂ (1 ml) was stirred for 1 h at 25° C. The mixture wasdiluted by Et₂O and then filtered. The concentrated crude product waschromatographed to give 5.2 mg of 35 (71.9%) as yellow crystal: mp138-140° C.; IR (KBr) 2959, 2892, 1683, 1616, 1549, 1441, 1360 cm⁻¹; ¹HNMR (CDCl₃) δ 1.14 (m, 2H), 1.35 (m, 2H), 2.06 (s, 3H), 4.02 (m, 2H),4.16 (m, 2H), 6.63 (dd, J=2.4,4.8 Hz, 1H), 6.76(d, J=4.8 Hz, 1H), 7.39(s, 1H); ¹³C NMR (CDCl₃) δ 187.6, 159.6, 140.3, 135.4, 131.0, 127.9,124.8, 106.2, 66.0, 33.4, 16.9, 12.9; MS m/z 230 (M⁺), 202,158; HRMS forC₁₄H₁₄O₃ calcd 230.0942, found 230.0948; U γ_(max) (methanol) 230 nm (e6543), 330 (e 3484).

EXAMPLE III

Synthesis of Compound 42

Compound 36.

To a solution of 27 (Example II) (37 mg, 0.18 mmol) in pyridine (3 ml)was added TESCl (0.25 ml, 0.624 mmol). The mixture was stirred at 60° C.for 0.5 h under N₂. After concentration and chromatography, it gave 50rag of 36 (87%) as colorless oil: IR (KBr) 2952, 2872, 1703, 1622, 1461,1414, 1226 cm⁻¹; ¹H NMR (CDCl₃) δ 0.58 (q, J=7.8 Hz, 6H),0.97 (m, ;10H), 1.25 (n, 2H), 1.58 (n, 1H), 1.85 (m, 2H), 1.98 (s, 3H), 2.42 (m,2H), 3.09 (b, 1H), 4.01 (d, J=3 Hz, 1H); ¹³C NMR (CDCl₃) 6206.0, 205.0,147.0, 128.6, 72.6, 43.0, 39.6, 32.1, 21.4, 19.6, 18.0, 11.5, 6.5, 4.5;MS m/z 320 (M⁺), 291, 259, HRMS for C₁₈H₂₈O₃Si calcd 320.1808, found320.1803.

Compound 37.

The solution of 36 (278 mg, 0.869 mmol) and phenylseleninic anhydride(320 mg, 0.889 mmol) in chlorobenzene (2.5 ml) was stirred at 95° C. for0.5 h under N₂. The mixture was then concentrated and chromatographed togive 58.7 mg of 36 and 131.2 mg of 37 (60.2%) as colorless gum: IR (KBr)2952, 2878, 1730, 1690, 1636, 1454, 1240 cm⁻¹; ¹H NMR (CDCl₃) δ 0.52 (q,J=7.8 Hz, 6H), 0.85 (t, J=7.8 Hz, 9H), 1.20 (m, 1H), 1.36 (m, 1H), 1.69(m, 1H), 1.82 (m, 1H), 2.06 (s, 3H), 3.58 (s, 1H), 4.26 (d, J=2.4 Hz,1H), 6.45 (dd, J=2.1, 6 Hz, 1H), 7.33 (dd, J=2.1, 6 Hz, 1H); ¹³C NMR(CDCl₃) δ 205.9, 195.3, 153.2, 144.3, 139.4, 127.7, 72.1, 47.3,32.4,20.1, 19.7, 11.4, 6.4, 4.4; MS m/z 318 (M⁺), 289, 261; HRMS forC₁₈H₂₆O₃Si calcd 318.1651, found 318.1658.

Compound 40.

To a solution of 37 (9.5 mg, 0.0299 mmol), CeCl₃.7H₂O (58.5 mg, 0.157mmol) in MeOH (0.3 ml) was added NaBH₄ (excess) at 25° C. It was stirredfor 30 min. Then the mixture was partitioned between Et₂O and saturatedNH₄Cl. The ether extract was dried by MgSO₄ and concentrated to givecrude product 38 as pale yellow oil.

To the solution of above 38 in CH₂Cl₂. (0.2 ml) was added Et₃N (5 ml,0.036 mmol) and MsCl (5 ml, 0.965 mmol) at 25° C. The mixture wasstirred for 5 min and then separated between Et₂O and saturated NaHCO₃.Then the ether extract was washed by saline and dried by MgSO₄. Afterconcentration, it was chromatographed to give 8.2 mg of 40 (90.3%) asyellow gum: IR (KBr) 3557, 3449, 2946, 2878, 1716, 1643, 1461, 1112cm⁻¹; ¹H NMR (CDCl₃) δ 0.66 (q, J=7.8 Hz, 6H), 0.87 (m, 2H), 0.98 (t,J=7.8 Hz, 9H), 1.26 (m, 2H), 1.86 (s, 3H), 2.55 (d, J=3.9 Hz, 1H), 3.24(s, 1H), 4.94 (d, J=2.1 Hz, 1H), 6.35 (m, 2H),. 6.46 (m, 1H); ¹³C NMR(CDCl₃) δ 148.9, 140.0, 130.4, 117.8, 117.5, 77.0,68.6, 61.9, 16.1,11.6,7.8, 6.8, 5.0; MS m/z 304 (Mt), 287, 275; HRMS for C₁₈H₂₈O₂Si calcd304.1859, found 304.1860.

Compound 41.

A solution of 40 (1.2 mg, 3.95 mmol) and Dess-Martin reagent (2.2 mg,5.19 mmol) in CH₂Cl₂ (0.2 ml) was stirred for 30 min at 25° C. Themixture was separated between Et₂O and 10% Na₂SO₃. Then the etherextract was washed by saline and dried by MgSO₄. After concentration, itwas chromatographed to give 1.1 mg of 41 (92.3%) as yellow gum: IR (KBr)2952, 2872, 1690, 1610, 1549, 1354, 1132 cm⁻¹; ¹H NMR (CDCl₃) δ 0.71 (q,J=7.8 Hz, 6H), 0.85 (m, 1H), 0.97 (t, J=7.8 Hz, 9H), 1.21 (m, 2H), 1.45(m, 1H), 2.08 (s, 3H), 4.50 (s, 1H), 6.66 (dd, J=2.4. 4.8 Hz, 1H), 6.72(d, J=5.1 Hz, 1H), 7.25 (s, 1H); ¹³C NMR (CDCl₃) δ 193.3. 161.2. 140.7,131.8, 131.2, 128.3, 122.8, 32.9, 17.1, 12.5, 10.3, 6.9, 5.2; MS m/z 302(M⁺), 273, 245; HRMS for C₁₈H₂₆O₂Si calcd 302.1702, found 302.1710; UVγ_(max)227 nm(e 15612), 323 nm (e 10720).

Compound 42.

To a solution of 41 (9.0 mg, 0.0298 mmol) in acetone (0.8 ml) and H₂O(0.4 ml) was added some p-TsOH. The mixture was stirred for 30 min. Thenit was partitioned between Et₂O and saturated NaHCO₃. The ether extractwas washed by saline and dried by MgSO₄ After concentration, it waschromatographed to give quantitative 42 as yellow gum: IR (KBr) 3449,3013, 2925, 1663, 1609, 1441, 1367, 1260 cm⁻¹; ¹H NMR (CDCl₃) δ 0.81 (m,1H), 1.25 (m, 1H), 1.36 (m, 1H), 1.44 (m, 1H), 2.12 (s, 3H), 3.82 (d,J=2.4 Hz, 1H), 4.55 (d, J=2.1 Hz, 1H), 6.70 (dd, J=2.7, 5.1 Hz, 1H),6.81 (t, 1H), 7.32 (s, 1H); ¹³C NMR (CDCl₃) δ 194.2, 162.2, 140.9,132.7, 131.4, 126.5, 124.1, 74.6, 32.8, 17.0, 12.7, 10.3; MS m/z 188(M⁺), 160, 145; HRMS for C₁₂H₁₂O₂ calcd 188.0837, found 188.0840; UVγ_(max)(methanol) 227 nm (e 13626), 323 nm (e 7474).

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

We claim:
 1. A compound of formula (IV):

wherein R′ and each R₉ are each independently (C₁-C₄)alkyl.
 2. Thecompound of claim 1, wherein each R₉ is CH₃.
 3. The compound of claim 1,wherein R′ is CH₃.
 4. The compound of claim 1, wherein R′ is CH₃ andeach R₉ is CH₃.